EP3107925B1 - Process for the production of 21-methoxy-11-beta-phenyl-19-nor-pregna-4,9-diene-3,20-dione derivatives - Google Patents

Process for the production of 21-methoxy-11-beta-phenyl-19-nor-pregna-4,9-diene-3,20-dione derivatives Download PDF

Info

Publication number
EP3107925B1
EP3107925B1 EP15708050.8A EP15708050A EP3107925B1 EP 3107925 B1 EP3107925 B1 EP 3107925B1 EP 15708050 A EP15708050 A EP 15708050A EP 3107925 B1 EP3107925 B1 EP 3107925B1
Authority
EP
European Patent Office
Prior art keywords
added
process according
solution
lithium
reaction mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP15708050.8A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP3107925A1 (en
Inventor
Sándor MAHÓ
Csaba SÁNTA
János CSÖRGEI
Gábor SZABÓ
Tamás SCHÄFER
Zoltán BÉNI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Nyrt
Original Assignee
Richter Gedeon Nyrt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Nyrt filed Critical Richter Gedeon Nyrt
Publication of EP3107925A1 publication Critical patent/EP3107925A1/en
Application granted granted Critical
Publication of EP3107925B1 publication Critical patent/EP3107925B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Definitions

  • the present invention relates to a new process for the synthesis of 21-methoxy-pregnane derivatives of formula (I), wherein the meaning of R is dimethylamino or acetyl group, using methoxymethyl lithium reagent, there is also disclosed the intermediate of formula (III), wherein the meaning of R' is 2-methyl-1,3-dioxolan-2-yl group.
  • the hydroxyl group in position 17 of the commercially available 3,3-[1,2-ethanediyl-bis-(oxy)]-17 ⁇ -hydroxy-estr-5(10),9(11)-dien-17 ⁇ -carbonitrile was silylated with (bromomethyl)dimethylsilyl chloride. Then the 17-silyloxy bromo compound was transformed into 21-bromo compound using lithium diisopropylamide at -78°C.
  • Introduction of the methoxy group in position 21 was carried out in a rather complicated, multistep process: via the 21-acetoxy and 21-hydroxy derivatives, using 6 equivalent excess of trimethyloxonium tetrafluoroborate salt together with proton sponge (SNAP reaction). On one hand this method is expensive, on the other hand the removal of the proton sponge is difficult, in many cases it requires the purification of the product in several steps.
  • Alkoxymethyl lithium reagent has not been used so far in the synthesis of steroids.
  • the present invention relates to a new process for the synthesis of 21-methoxy-pregnane derivatives of formula (I), which has less steps as the known ones described above, it is industrially realizable, safe and economical.
  • the process differs from the one described in the patent application No. WO2009001148 , that the introduction of the side-chain in position 17 was carried out in a different way, with special regard to the introduction of the methoxy group in position 21.
  • introduction of the methoxy group can be carried out in a more simple way, in less steps than in the processes described above, if the compounds of formula (III) or (IV) are reacted with methoxymethyl lithium - synthesized preferably in situ - under proper conditions.
  • the present invention relates to a new process ( Figure 3.) for the synthesis of 21-methoxy-pregnane derivatives of formula (I) wherein the meaning of R is dimethylamino or acetyl group, to the synthesis of the methoxymethyl lithium reagent used in the process, there is also disclosed herein the intermediate of formula (III), wherein the meaning of R' is 2-methyl-1,3-dioxolan-2-yl group.
  • the hydroxyl group in position 5 of compound of formula (IV), wherein the meaning of R' is dimethylamino or 2-methyl-1,3-dioxolan-2-yl group, and synthesized according to method described in patent application No. WO2009001148 is silylated with chloro-trimethylsilane in the presence of imidazole in a halogenated solvent or tetrahydrofuran or toluene, preferably in dichloromethane, at room temperature to yield the compound of formula (III), wherein the meaning of R' is as described above.
  • the methoxymethyl lithium reagent is synthesized.
  • a condensed or conjugated aromatic hydrocarbon in given case substituted with alkyl groups for example naphthalene, alklylnaphthalene, anthracene, 4,4'-di-tertbutyl-biphenyl, preferably biphenyl, is dissolved in an ether, aliphatic or aromatic hydrocarbon or formaldehyde dialkylacetal type solvent, for example tetrahydrofuran, methyltetrahydrofuran, diethyl ether, diisopropyl ether, methyl-tertbutyl ether, toluene, dimethoxyethane, diethoxyethane, preferably tetrahydrofuran, and lithium metal is added to the so obtained solution under inert atmosphere.
  • alkyl groups for example naphthalene, alklylnaphthalene, anthracene, 4,4'-di-tertbuty
  • the reaction mixture is vigorously stirred for 0.5-5 hours, preferably for 3 hours, until the lithium is dissolved at 0-20°C, preferably at 5-10°C. Then the solution is cooled to (-78)-(-40)°C, preferably to -55°C, and methoxymethyl chloride in itself or in a solution of any of the above mentioned solvents is added to the mixture in such a rate as to keep the reaction temperature between (-78)-(-30)°C, preferably between (-55)-(-40)°C.
  • the solution of compound of formula (III) or (IV) is added to the so obtained solution at a temperature between (-78)-(-30)°C, preferably between (-55)-(-50)°C.
  • the reaction mixture is stirred at a temperature between (-78)-(-30)°C, preferably between (-48)-(-52)°C for 0.5-3 hours, preferably for 2 hours.
  • water is added to the reaction mixture in such a rate as to keep the reaction temperature below 0°C, preferably at -10°C.
  • the reaction mixture is vigorously stirred for 10-120 min, preferably for 30 min, while the temperature is allowed to rise to 10-15°C.
  • the solution containing the protected intermediate is treated with a strong acid, for example hydrochloric acid, sulphuric acid, p-toluenesulphonic acid, perchloric acid, methanesulphonic acid, phosphoric acid, potassium hydrogensulphate, preferably sodium hydrogensulphate, to yield the solution of the compound of formula (II), from which the compound of formula (II), wherein the meaning of R is dimethylamino or acetyl group, is isolated in a suitable way.
  • the obtained product in given case is purified by chromatography.
  • the hydroxyl group in position 17 is acetylated according to the method described in patent application No. WO2009001148 to yield the final product of formula (I), wherein the meaning of R is as described above.
  • the temperature of the reaction mixture was kept at 15-20°C. After 2 hours stirring was stopped, and after settling the phases were separated, the upper organic phase was washed with 2x100 ml of about 10v/v% sulphuric acid, and the water phases were combined. The combined water phases containing the steroid were extracted with 2x100 ml of cyclohexane. Then the water phase was added to a solution of 83.73 g of sodium carbonate in 3 L of water over a period of 10-15 min. The precipitated crystals were filtered off after 30 min stirring, washed several times with water until neutral pH. The product was dried at 40°C in vacuum oven until constant weight to yield 14.5 g (97.44%) of the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP15708050.8A 2014-02-17 2015-02-16 Process for the production of 21-methoxy-11-beta-phenyl-19-nor-pregna-4,9-diene-3,20-dione derivatives Active EP3107925B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU1400080A HU230381B1 (hu) 2014-02-17 2014-02-17 Ipari eljárás szteroid intermedier előállítására
PCT/IB2015/051124 WO2015121840A1 (en) 2014-02-17 2015-02-16 Process for the production of 21 -methoxy-11 -beta-phenyl-19-nor-pregna-4,9-diene-3,20-dione derivatives

Publications (2)

Publication Number Publication Date
EP3107925A1 EP3107925A1 (en) 2016-12-28
EP3107925B1 true EP3107925B1 (en) 2018-05-16

Family

ID=89991401

Family Applications (1)

Application Number Title Priority Date Filing Date
EP15708050.8A Active EP3107925B1 (en) 2014-02-17 2015-02-16 Process for the production of 21-methoxy-11-beta-phenyl-19-nor-pregna-4,9-diene-3,20-dione derivatives

Country Status (7)

Country Link
US (1) US9683010B2 (zh)
EP (1) EP3107925B1 (zh)
CN (1) CN106414475B (zh)
EA (1) EA032651B1 (zh)
ES (1) ES2682939T3 (zh)
HU (2) HU230381B1 (zh)
WO (1) WO2015121840A1 (zh)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015049637A1 (en) * 2013-10-01 2015-04-09 Richter Gedeon Nyrt. Industrial process for the synthesis of ulipristal acetate and its 4'-acetyl analogue

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6900193B1 (en) 1996-05-01 2005-05-31 The United States Of America As Represented By The Department Of Health And Human Services Structural modification of 19-norprogesterone I: 17-α-substituted-11-β-substituted-4-aryl and 21-substituted 19-norpregnadienedione as new antiprogestational agents
EP0900234B1 (en) 1996-05-01 2000-07-05 THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by the SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES 21-substituted progesterone derivatives as new antiprogestational agents
EP1242444B1 (en) 1999-12-29 2005-07-20 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Process for preparing 17alpha-acetoxy-11beta- 4-n,n-(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the process, and processes for preparing such intermediates
ES2546291T3 (es) 2000-03-17 2015-09-22 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services 17-Alfa-sustituida, 11-beta-sustituida-4-arilo y 21-sustituida 19-norpregnadienodionas como agentes antiprogestacionales
HU228636B1 (en) * 2007-06-27 2013-04-29 Richter Gedeon Nyrt Industrial method for the synthesis of 17-acetoxy-11betha-4[-(dimethylamino)-phenyl]-21-methoxy-19-norpregna-4,9-dien-3,20-dione and the key intermediates of the process
TWI539953B (zh) * 2008-04-28 2016-07-01 瑞波若斯治療學公司 用於治療乳癌之組成物和方法
TWI477276B (zh) * 2008-04-28 2015-03-21 Repros Therapeutics Inc 抗黃體素給藥方案

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015049637A1 (en) * 2013-10-01 2015-04-09 Richter Gedeon Nyrt. Industrial process for the synthesis of ulipristal acetate and its 4'-acetyl analogue

Also Published As

Publication number Publication date
CN106414475B (zh) 2018-04-10
EA032651B1 (ru) 2019-06-28
HUE039403T2 (hu) 2018-12-28
US20160326211A1 (en) 2016-11-10
EP3107925A1 (en) 2016-12-28
HUP1400080A2 (en) 2015-09-28
US9683010B2 (en) 2017-06-20
ES2682939T3 (es) 2018-09-24
EA201691661A1 (ru) 2016-12-30
HU230381B1 (hu) 2016-03-29
CN106414475A (zh) 2017-02-15
WO2015121840A1 (en) 2015-08-20

Similar Documents

Publication Publication Date Title
EP2774933B1 (en) Ulipristal acetate preparation method and intermediate thereof
CA2851330C (en) Process for preparing 17-substituted steroids
JP5061061B2 (ja) ９α，２１−ジハロ−プレグナン−１１β，１７α−ジオール−２０−オンの１７−エステルの調製のためのプロセス
EP2266998B1 (en) Process for obtaining 17-spirolactones in steroids
JP6100798B2 (ja) １６−置換型−１７−ケトステロイド類のアルキニル化方法
EP3052513B1 (en) Industrial process for the synthesis of ulipristal acetate and its 4'-acetyl analogue
AU775831B2 (en) Process for preparing 17alpha-acetoxy-11beta-(4-N,N-(dimethylamino)phenyl)-21- methoxy-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the process, and processes for preparing such intermediates
EP3107925B1 (en) Process for the production of 21-methoxy-11-beta-phenyl-19-nor-pregna-4,9-diene-3,20-dione derivatives
JP7264569B2 (ja) １１－メチレンステロイドの製造のための方法および新規な中間体
EP1935898B1 (en) Process for the preparation of 17alpha-cyanomethyl-17beta-hydroxy steroids
EP0053845B1 (en) 17-beta-ethynylsteroids and process for preparing same
WO2005095431A1 (ja) ５α－プレグナン誘導体の製造方法
EP3083655B1 (en) A process for the production of 19-norpregn-4-en-3,20-dione-17.alpha.-ol (gestonorone) and intermediates therefor.
TWI535732B (zh) 一種製備去氧膽酸的方法
JPS623840B2 (zh)
WO1991014700A2 (en) PROCESS FOR 9α-HYDROXY STEROID DEHYDRATION
JP2714392B2 (ja) ステロイド誘導体の製造法
IL38143A (en) Process for the preparation of 11,12-enolates of 9alpha-halo-11-keto steroids and of 9alpha,12-dihalo or 9alpha,12,12,12-trihalo 11-keto(or11-hydroxy)steroids
NZ717638B2 (en) Industrial process for the synthesis of ulipristal acetate and its 4'-acetyl analogue
JPS6352633B2 (zh)

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20160915

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

RIN1 Information on inventor provided before grant (corrected)

Inventor name: MAHO, SANDOR

Inventor name: SANTA, CSABA

Inventor name: SZABO, GABOR

Inventor name: CSOERGEI, JANOS

Inventor name: SCHAEFER, TAMAS

Inventor name: BENI, ZOLTAN

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20171026

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602015011150

Country of ref document: DE

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 999433

Country of ref document: AT

Kind code of ref document: T

Effective date: 20180615

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20180516

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2682939

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20180924

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180816

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180816

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180817

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 999433

Country of ref document: AT

Kind code of ref document: T

Effective date: 20180516

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E039403

Country of ref document: HU

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602015011150

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20190219

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20200219

Year of fee payment: 6

Ref country code: DE

Payment date: 20200219

Year of fee payment: 6

Ref country code: HU

Payment date: 20200131

Year of fee payment: 6

Ref country code: ES

Payment date: 20200322

Year of fee payment: 6

Ref country code: IT

Payment date: 20200225

Year of fee payment: 6

Ref country code: GB

Payment date: 20200219

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20200219

Year of fee payment: 6

Ref country code: LU

Payment date: 20200219

Year of fee payment: 6

Ref country code: BE

Payment date: 20200219

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180917

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MT

Payment date: 20200123

Year of fee payment: 6

Ref country code: FR

Payment date: 20200219

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180916

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602015011150

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20210216

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20210228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210228

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210217

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210216

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210216

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210228

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210216

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210901

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210216

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20220511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210216

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180516

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210217

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210228